1. Field of the Invention
This invention is directed to a method for development of therapeutics that selectively enhance fatty acid oxidation, increase energy production, and reduce adiposity while preserving lean mass, through the pharmacological stimulation of CPT-1 activity.
2. Review of Related Art
Cerulenin treatment of MCF-7 human breast cancer cells in vitro significantly inhibits fatty acid oxidation, probably through increased levels of malonyl-CoA (Loftus, et al. (2000) Science, 288:2379-2381). C75 is a member of a family of α-methylene-γ-butyrolactones which are known inhibitors of fatty acid synthase (FAS) (Kuhajda, et al. (2000) Proc. Natl. Acad Sci USA, 97:3450-3454). Treatment of mice with C75 leads to inhibition of hepatic fatty acid synthesis and high levels of malonyl-CoA (Loftus, et al. (2000); Pizer, et al. (2000) Cancer Res., 60:213-218). In the brain, C75 reduces the expression of hypothalamic neuropeptide-Y (NPY) leading to reversible inanition (Loftus, et al, 2000). During in vivo treatment of ob/ob mice with C75 there was profound loss of fat in the liver and peripheral tissues despite the increased levels of hepatic malonyl-CoA (Loftus, et al., 2000).
Malonyl-CoA is a potent inhibitor of fatty acid oxidation through its action as an inhibitor of carnitine-palmitoyl-transferase-1 (CPT-1) (Witters, et al. (1992) J. Biol. Chem., 267:2864-2867). CPT-1 enables the entry of long-chain acyl-CoA's into the mitochondria for fatty acid oxidation. When treated with FAS inhibitors, genetically and diet-induced obese mice undergo a selective and significant loss of adipose tissue despite the high levels of malonyl-CoA induced by FAS inhibition. Since malonyl-CoA is a potent inhibitor of fatty acid oxidation through its inhibition of carnitine palmitoyltransferase-1 (CPT-1, E.C. 2.3.1.21), the rapid and selective loss of adipose tissue was surprising. High systemic levels of malonyl-CoA would be expected to inhibit fatty acid oxidation leading instead to a selective loss of lean mass during C75 induced inanition.